DESCRIPTION (Applicant's abstract): Sleep disordered breathing is characterized by upper airway obstruction and hypoventilation during sleep. Obstructive sleep apnea is the most common form of sleep disordered breathing, and is due to recurrent collapse of the upper airway during sleep. The major risk factors for the development of sleep disordered breathing are obesity, male gender, and increasing age. The precise mechanism for upper airway obstruction and hypoventilation during sleep are unknown. Currently, it is believed that these events are due to alterations in mechanical factors or neuromuscular control precipitated by obesity. It is our overall hypothesis that obesity is associated with progressive defects in reflex mechanisms that lead to upper airway obstruction and hypoventilation during sleep. Moreover, we have evidence that weight loss ameliorates sleep disordered breathing, and we now wish to determine whether this improvement is due to restoration of reflex control mechanisms in the human and to determine the neurohumoral mechanisms in a murine model of the syndrome. In a series of cross sectional and longitudinal experiments, we will examine the effects of obesity on upper airway and ventilatory function, and its modulation by weight loss. In Specific Aim 1, we hypothesize that the response in upper airway pressure-flow relationships to electrical stimulation of the hypoglossal nerve is more effective (a) when the locus of collapse is in the oropharyngeal region and (b) in patients with a lower body mass index. In Specific Aim 2, we hypothesize that a defect in reflex responses to nasal pressure and CO2 exists in (a) patients with obstructive sleep apnea vs. normal controls, and (b) that this defect depends upon the degree of obesity. In Specific Aim 3, we hypothesize that weight loss will restore reflex responses to nasal pressure and CO2. In Specific Aim 4, we hypothesize that (a) changes in neuroventilatory control with weight loss requires an intact leptin axis, and (b) the protective effect of leptin is enhanced in females vs. males. This proposal develops and utilizes methods specifically to quantitate the mechanical and neuromuscular basis for disturbances in upper airway neuromuscular control in humans (Specific Aims 1-3). Complementary experiments in a murine model are proposed in order to probe neurohumoral mechanisms responsible for alterations in ventilatory control (Specific Aim 4). The proposed studies are designed to elucidate the pathophysiologic basis and to explore novel treatments for sleep disordered breathing.